Treating sexual desire disorders with flibanserin

ABSTRACT

The invention relates to the use of flibanserin, or a pharmaceutically acceptable acid addition salt thereof, for the treatment of disorders of sexual desire.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 16/125,883, filed Sep. 10, 2018, which is a continuation ofU.S. patent application Ser. No. 15/694,317, filed Sep. 1, 2017 (NowU.S. Pat. No. 10,098,876), which is a continuation of U.S. patentapplication Ser. No. 15/270,167, filed Sep. 20, 2016 (Now U.S. Pat. No.9,782,403), which is a continuation of U.S. patent application Ser. No.14/640,055, filed Mar. 6, 2015 (Now U.S. Pat. No. 9,468,639), which is acontinuation of U.S. patent application Ser. No. 14/269,373, filed May5, 2014, which is a continuation of U.S. patent application Ser. No.13/920,354, filed Jun. 18, 2013, which is a continuation of U.S. patentapplication Ser. No. 13/551,036, filed Jul. 17, 2012, which is acontinuation of U.S. patent application Ser. No. 11/524,268, filed Sep.21, 2006 (Now U.S. Pat. No. 8,227,471), which is a continuation of U.S.patent application Ser. No. 10/272,603, filed Oct. 16, 2002 (Now U.S.Pat. No. 7,151,103), which claims priority to U.S. Provisional PatentApplication No. 60/348,911, filed Oct. 23, 2001 and European PatentApplication No. EP 01 1250 20.6, filed Oct. 20, 2001, the disclosures ofeach of which are incorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The invention relates to the use of flibartserin for the preparation ofa medicament for the treatment of disorders of sexual desire.

BACKGROUND OF THE INVENTION

The compound1-[2-(4-(3-trifluoromethyl-phenyl)piperazin-1-yl)ethyl]-2,3-dihydro-1H-benzimidazol-2-one(flibanserin) is disclosed in form of its hydrochloride in EuropeanPatent Application EP-A-526434 and has the following chemical structure.

Flibanserin shows affinity for the 5-HT1A and 5-HT2-receptor. It istherefore a promising therapeutic agent for the treatment of a varietyof diseases, for instance depression, schizophrenia, and anxiety.

DETAILED DESCRIPTION OF THE INVENTION

In studies of male and female patients suffering from sexual dysfunctionit has been found that flibanserin optionally in form of thepharmacologically acceptable acid addition salts thereof displays sexualdesire enhancing properties. Accordingly, the instant invention relatesto the use of flibanserin, optionally in of the pharmacologicallyacceptable acid addition salts thereof for the preparation of amedicament for the treatment of disorders of sexual desire.

In a preferred embodiment the invention relates to the use offlibanserin, optionally in form of the pharmacologically acceptable acidaddition salts thereof for the preparation of a medicament for thetreatment of disorders selected from the group consisting of HypoactiveSexual Desire Disorder, loss of sexual desire, lack of sexual desire,decreased sexual desire, inhibited sexual desire, loss of libido, libidodisturbance, and frigidity.

Particular preferred according to the invention is the use offlibanserin, optionally in form of the pharmacologically acceptable acidaddition salts thereof for the preparation of a medicament for thetreatment of disorders selected from the group consisting of HypoactiveSexual Desire Disorder, loss of sexual desire, lack of sexual desire,decreased sexual desire, inhibited sexual desire.

In a particularly preferred embodiment the invention relates to the useof flibanserin, optionally in form of the pharmacologically acceptableacid addition salts thereof for the preparation of a medicament for thetreatment of disorders selected from the group of Hypoactive SexualDesire Disorder and loss of sexual desire.

The observed effects of flibanserin can be achieved in men and women.However, according to a further aspect of the invention the use offlibanserin optionally in form of the pharmacologically acceptable acidaddition salts thereof for the preparation of a medicament for thetreatment of female sexual dysfunction is preferred.

The beneficial effects of flibanserin can be observed regardless ofwhether the disturbance existed lifelong or was acquired, andindependent of etiologic origin (organic—both, physically and druginduced—, psychogen, a combination of organic—both, physically and druginduced—, and psychogen, or unknown).

Flibanserin con optionally used in form of its pharmaceuticallyacceptable acid addition salts. Suitable acid addition salts include forexample those of the acids selected from, succinic acid, hydrobromicacid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid,lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid,tartaric acid and citric acid. Mixtures of the abovementioned acidaddition salts may also be used. From the aforementioned acid additionsalts the hydrochloride and the hydrobromide, particularity thehydrochloride, are preferred.

Flibanserin, optionally used in form of its pharmaceutically acceptableacid addition salts, may be incorporated into the conventionalpharmaceutical preparation in solid, liquid or spray form. Thecomposition may, for example, be presented in a form suitable for oral,rectal, parenteral administration or for nasal inhalation: preferredforms includes for example, capsules, tablets, coated tablets, ampoules,suppositories and nasal spray. The active ingredient may be incorporatedin excipients or carriers conventionally used in pharmaceuticalcompositions such as, for example, talc, arabic gum, lactose, gelatine,magnesium stearate, corn starch, acqueous or non acqueous vehicles,polyvynil pyrrolidone, semisynthetic glicerides of fatty acids,benzalconium chloride, sodium phosphate, EDTA, polysorbate 80. Thecompositions are advantageously formulated in dosage units, each dosageunit being adapted to supply a single dose of the active ingredient. Thedosis range applicable per day is between 0.1 to 400, preferably between1.0 to 300, more preferably between 2 to 200 mg.

Each dosage unit may conveniently contain from 0.01 mg to 100 mg,preferably from 0.1 to 50 mg.

Suitable tablets may be obtained, for example, by mixing the activesubstance(s) with known excipients, for example inert diluents such ascalcium carbonate, calcium phosphate or lactose, disintegrants such ascorn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

Coated tablets may be prepared accordingly by coating cores producedanalogously to the tablets with substances normally used for tabletcoatings, for example collidone or shellac, gum arabic, talc, titaniumdioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number or layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

Syrups or elixirs containing the active substances or combinationsthereof according to the invention may additionally contain a sweetenersuch as saccharine, cyclamate, glycerol or sugar and a flavour enhancer,e.g of a flavouring such as vanilline or orange extract. They may alsocontain suspension adjuvants or thickeners such as sodium carboxymethylcellulose, wetting agents such as, for example, condensation products offatty alcohols with ethylene oxide, or preservatives such asp-hydroxybenzoates.

Solutions for injection are prepared in the usual way, e.g of with theaddition of preservatives such as p-hydroxybenzoates, or stabiliserssuch as alkali metal salts of ethylenediamine tetraacetic acid, andtransferred into injection vials or ampoules.

Capsules containing one or more active substances or combinations ofactive substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

Suitable suppositories may be made for example by mixing with carriersprovided for this purpose, such as neutral fats or polyethyleneglycol orthe derivatives thereof.

The Examples which follow illustrate the present invention withoutrestricting its scope:

Examples of Pharmaceutical Formulations

A) Tablets per tablet flibanserin hydrochloride 100 mg lactose 240 mgcorn starch 340 mg polyvinylpyrrolidone 45 mg magnesium stearate 15 mg740 mg

The finely ground active substance, lactose and some of the corn starchare mixed together. The mixture is screened, then moistened with asolution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size.

B) Tabletsper tablet flibanserin hydrochloride 80 mg corn starch 190 mglactose 55 mg microcrystalline cellulose 35 mg polyvinylpyrrolidone 15mg sodium-carboxymethyl starch 23 mg magnesium stearate 2 mg 400 mg

The finely ground active substance, some of the corn starch, lactose,microcrystalline cellulose and polyvinylpyrrolidone are mixed together,the mixture is screened and worked with the remaining corn starch andwater to form a granulate which is dried and screened. The sodiumcarboxy-methyl starch and the magnesium stearate are added and mixed inand the mixture is compressed to form tablets of a suitable size.

C) Coated tablets per coated tablet flibanserin hydrochloride 5 mg cornstarch 41.5 mg lactose 30 mg polyvinylpyrrolidone 3 mg magnesiumstearate 0.5 mg 80 mg

The active substance, corn starch, lactose and polyvinylpyrrolidone arethoroughly mixed and moistened with water. The moist mass is pushedthrough a screen with a 1 mm mesh size, dried at about 45° C. and thegranules are then passed through the same screen. After the magnesiumstearate has been mixed in, convex tablet cores with a diameter of 6 mmare compressed in a tablet-making machine. The tablet cores thusproduced are coated in known manner with a covering consistingessentially of sugar and talc. The finished coated tablets are polishedwith wax.

D) Capsules per capsule flibanserin hydrochloride 1 50 mg Corn starch268.5 mg Magnesium stearate 1.5 mg 420 mg

The substance and corn starch are mixed and moistened with water. Themoist mass is screened and dried. The dry granules are screened andmixed with magnesium stearate. The finished mixture is packed into size1 hard gelatine capsules.

E) Ampoule solution flibanserin hydrochloride 50 mg sodium chloride 50mg water for inj. 5 ml

The active substance is dissolved in water at its own pH or optionallyat pH 5.5 to 6.5 and sodium chloride is added to make it isotonic. Thesolution obtained is filtered free from pyrogens and the filtrate istransferred under aseptic conditions into ampoules which are thensterilised and sealed by fusion.

F) Suppositories flibanserin hydrochloride 50 mg solid fat 1650 mg 1700mg

The hard fat is melted. At 40° C. the ground active substance ishomogeneously dispersed. It is cooled to 3° C. and poured into slightlychilled suppository moulds.

The invention claimed is:
 1. A method of treating a female hypoactivesexual desire disorder in a human adult patient, comprising orallyadministering a therapeutically effective amount of flibanserin to thepatient to treat the female hypoactive sexual desire disorder.
 2. Themethod according to claim 1, wherein the amount administered is betweenabout 0.1 mg and 400 mg per day of flibanserin.
 3. The method accordingto claim 1, wherein the amount administered is between about 1 mg and300 mg per day of flibanserin.
 4. The method according to claim 1,wherein the amount administered is in a dosage unit containing betweenabout 0.01 mg and 100 mg of flibanserin.
 5. The method according toclaim 1, wherein the amount administered is in a dosage unit containingabout 100 mg.
 6. A method of treating a female hypoactive sexual desiredisorder in a human adult patient, comprising orally administering atablet comprising a therapeutically effective amount of flibanserin tothe patient to treat the female hypoactive sexual desire disorder. 7.The method according to claim 6, wherein the amount administered isbetween about 0.1 mg and 400 mg per day of flibanserin.
 8. The methodaccording to claim 6, wherein the tablet comprises about 0.01 mg to 100mg of flibanserin.
 9. The method according to claim 6, wherein thetablet comprises about 100 mg flibanserin.
 10. The method according toclaim 6, wherein the tablet further comprises one or more excipients orcarriers.
 11. The method according to claim 10, wherein the one or moreexcipients or carriers comprise at least one inert diluent.
 12. Themethod according to claim 11, wherein the at least one inert diluent isselected from calcium carbonate, calcium phosphate, lactose, andcombinations thereof.
 13. The method according to claim 10, wherein theone or more excipients or carriers comprise at least one lubricant. 14.The method according to claim 13, wherein the at least one lubricant isselected from the group consisting of magnesium stearate, talc, andcombinations thereof.
 15. The method according to claim 10, wherein theone or more excipients or carriers comprise at least one distintegrant.16. The method according to claim 15, wherein the at least onedisintegrant is selected from corn starch, alginic acid, andcombinations thereof.
 17. The method according to claim 10, wherein theone or more excipients or carriers comprise at least one binder.
 18. Themethod according to claim 17, wherein the at least one binder isselected from starch, gelatin, and combinations thereof.
 19. The methodaccording to claim 10, wherein the one or more excipients or carrierscomprise at least one agent for delaying release.
 20. The methodaccording to claim 19, wherein the at least one agent for delayingrelease is selected from carboxymethyl cellulose, cellulose acetatephthalate, polyvinyl acetate, and combinations thereof.
 21. The methodaccording to claim 6, wherein the tablet further comprises one or moresweeteners, one or more flavor enhancers, preservatives, or acombination thereof.
 22. The method according to claim 6, wherein thetablet further comprises magnesium stearate, talc, and microcrystallinecellulose.
 23. The method according to claim 22, wherein the tabletfurther comprises one or both of lactose and sodium-carboxymethylstarch.
 24. The method according to claim 10, wherein the tabletcomprises a compressed mixture of flibanserin and the one or moreexcipients or carriers.
 25. The method according to claim 6, wherein thetablet is uncoated.